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Riboflavin transporter deficiency
A syndromic genetic deafness characterized by a peripheral and cranial neuropathy, neuronal loss in anterior horns and atrophy of spinal sensory tracts, causing muscle weakness, sensory loss, diaphragmatic paralysis and respiratory insufficiency, and multiple cranial nerve deficits such as sensorineural hearing loss, bulbar symptoms, and loss of vision due to optic atrophy. Depending on the transporter affected, Riboflavin transporter deficiency 2 (RFVT2) and Riboflavin transporter deficiency 3 (RFVT3) are distinguished.
ORPHA:97229Classification level: Disorder
- Brown-Vialetto-van Laere syndrome
- Sensorineural hearing loss-pontobulbar palsy syndrome
- Prevalence: <1 / 1 000 000
- Inheritance: Autosomal recessive
- Age of onset: Childhood, Infancy, Adolescent, Adult
- ICD-10: G12.1
- OMIM: 211500 211530 614707
- UMLS: C0796274
- MeSH: C537111
- GARD: 9993
- MedDRA: -
Riboflavin transporter deficiency (RTD) has been reported in more than 100 genetically diagnosed cases to date.
RTD onset may occur from early infancy until adulthood, with a more severe presentation at a younger age. The most frequent presenting symptoms are cranial neuropathy, sensory ataxia, muscle weakness and respiratory insufficiency due to diaphragmatic paralysis. The cranial neuropathy leads to sensorineural hearing loss, loss of vision due to optic atrophy, dysarthria, dysphagia, feeding problems, facial weakness and eye movement impairments. Peripheral neuropathy in combination with anterior horn cell dysfunction and atrophy of the sensory tracts in the spinal cord causes muscle weakness with atrophy and (sensory) ataxia. Diaphragmatic paralysis in combination with general muscle weakness may rapidly lead to respiratory insufficiency, especially in infants and young children. Often, feeding through a nasogastric tube or gastrostomy device and artificial ventilation and tracheotomy are required. If untreated, RTD is progressive and often fatal. Sensory ataxia and optic atrophy seem more prevalent in RFVT2 than RFVT3 deficient patients.
Riboflavin (Vitamin B2) is a water-soluble vitamin that is essential for normal metabolism as the sole precursor for cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). In RTD transport of riboflavin in different tissues is severely hampered leading to cellular flavin deficiency. As flavins play an important role in mitochondrial function, mitochondrial dysfunction might act as a pathomechanism contributing to neurodegeneration in RTD. Pathogenic biallelic mutations in the genes SLC52A2 and SLC52A3 that encode riboflavin transporters RFVT2 and RFVT3 cause RTD2 and RTD3.
Diagnosis is only possible through mutational analysis of all genes coding for riboflavin transporters (RFVT1, RFVT2 and RFVT3). Biochemical tests can show abnormalities such as abnormal (MADD like) plasma acylcarnitine profiles, abnormal urine organic acids and decreased plasma flavin levels; however in approximately 50% of patients normal results are found. Magnetic resonance imaging (MRI) is normal in the large majority of RTD patients. Electrophysiological testing (EMG) can show findings consistent with a sensorimotor axonal neuropathy with signs of anterior horn cell dysfunction, but normal results can also be observed.
Differential diagnosis include neuromuscular diseases like some forms of congenital or mitochondrial myopathy and rapidly progressive neuropathies.
Prenatal diagnosis is possible if family mutations in the RFVT2 or RFVT3 genes are known.
Inheritance is autosomal recessive. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 25% risk of passing the mutation to offspring.
Management and treatment
Riboflavin supplementations is lifesaving. Therefore, treatment with daily administration of a high dose oral riboflavin supplementation (20-70 mg/kg per day in 3 doses) should be started immediately upon suspicion of RTD and continued lifelong. Oral riboflavin is well tolerated with minimal side effects. Symptomatic treatment must be addressed promptly in early onset cases: assisted ventilation, tracheostomy when necessary, and maintenance of nutrition via gastrostomy may be required. Regular clinical evaluation during the course of treatment must be accompanied by neurological examination, evaluation of hearing and vision, respiratory function and skeletal deformities like scoliosis. Depending on the symptoms, physical and speech therapy should be initiated. In case of hearing loss, cochlear implants have proven highly successful in RTD.
If untreated, RTD is progressive and can be fatal in the majority of patients, with respiratory insufficiency as the main cause of death. Severity and rate of progression vary between patients. When treated with high doses of riboflavin suppletion, the majority of patients show improvement over time, and early treated patients may fully recover and develop normally. Clinical improvement may weeks to months after the start of treatment, therefore riboflavin treatment must be continued in all suspected or confirmed RTD patients. Some patients with irreversible damage may show stabilization but no improvement of symptoms. No deaths have been reported in riboflavin-treated RTD patients.